A strategy for constructing bicyclic lactam amino acid building blocks with imidazole sidechains is reported. The synthetic route described utilizes an electrochemical amide oxidation to functionalize a proline derivative, and then a sequential cyclization-rearrangement strategy to construct a substituted six-membered ring lactam. Alternatively, the seven-membered ring lactams were obtained without rearrangement when electron withdrawing groups were present beta to the amide carbonyl.

The study of intramolecular anodic olefin coupling reactions arising from diene substrates having an allylic alkoxy group have been studied. In all cases, the coupling reactions proceeded smoothly without elimination of the allylic alkoxy group. In addition, the reactions were found to afford five-membered ring products in a diastereoselective fashion. Substrates having both cis- and trans-disubstituted allyl silane olefin participants led to different ratios of products indicating that the cyclization reactions were under kinetic control.

Intramolecular anodic olefin coupling reactions involving electron-rich aryl rings were examined and shown to afford fused bicyclic products. When alkoxysubstituted phenyl rings were used, the reactions benefited from the use of either controlled potential electrolysis conditions or a vinyl sulfide initiating group. Coupling reactions involving heteroatomic aryl rings also led to good yields of cyclized product.

In an effort to develop electrochemical methods for directly initiating oxidative cyclization reactions, the anodic oxidation of bis enol ether substrates has been examined. The reactions were found to lead to the formation of five-, six-, and seven-membered-ring 1,4-dicarbonyl equivalents. The reactions were not found to be useful for generating larger ring sizes. Both alkyl and silyl enol ether substrates were found to be compatible with the conditions required for carbon-carbon bond formation. Cyclic voltammetry studies indicated that the cyclizations were fast and that the reactions happened at or near the electrode surface. Finally, the cyclization reactions were shown to be compatible with the formation of quaternary carbons, even when carbon-carbon bond formation involved the generation of two vicinal quaternary carbons.

The utility of intramolecular anodic olefin coupling reactions for effecting carbon-carbon bond formation has been examined. All of the successful cyclizationsstudied utilized either an alkyl or silyl enol ether as one of the participating olefins. The enol ethers could be coupled to simple alkyl olefins, styrenes, and allylsilanes in isolated yields ranging from 57 to 84%. The reactions were found to be effective for generating both five- and six-membered rings. The best conditions for cyclization utilized a reticulated vitreous carbon anode, constant-current conditions in an undivided cell, and a lithium perchlorate in either 50% methanol/tetrahydrofuran or 20% methanol/dichloromethane electrolyte solution. The use of an allylsilane as one of the participating olefins allowed for the regiospecific formation of olefinic products. In addition to the olefinic products, these reactions produced a small amount of a cyclized ether product in which the silyl group had not been eliminated. Deuterium-labeling studies showed that at least half of this ether byproduct arose from intramolecular migration of the methoxy group that was initially part of the starting enol ether to the carbon j to the silyl group. Intramolecular migration reactions of this type were found to participate in a number of the reported cyclization reactions.

The anodic oxidationsof amides in the presence of mono-, di-, and trialkoxyphenyl rings were examined. Although literature reduction potentials suggest that these oxidations would lead to either selective aromatic ring oxidation or mixtures, the chemoselectivity of the reactions was found to be dependent on the substitution pattern of the phenyl ring. For example, the anodic oxidations of ((3-methoxyphenyl)acetyl)pyrrolidine, ((2-methoxy-phenyl)acetyl)pyrrolidine, ((3-methoxy-4-(pivaloyloxy)phenyl)acetyl)pyrrolidine, and ((3,5-dimethoxy-4-(piva-1oyloxy)phenyl)acetyl)pyrrolidine all led to selective methoxylation of the pprolidine ring. The anodic oxidations and of (4-methoxypheny1)acetyl)pyrrolidine ((3,4-dimethoxyphenyl)acetyl)pyrrolidineled to selective methoxylation of the benzylic carbon. Mechanistic studies indicate that both amide and aryl oxidation processes compete under the reaction conditions, but that intramolecular electron transfer leads to the selective formation of products. Evidence for this mechanism was obtained by examining the cyclic voltammogram of ((3-methoxypheny1)-acetyl)pyrrolidine, competition studies, and the preparative electrolysis of (4-methoxypheny1)dimethyl-acety1)pyrrolidine. The methoxylated amides were cyclized to form tricyclic amides using titanium tetrachloride.

The use of allylsilanes as directing groups in the intramolecular electrochemical coupling of electron rich olefins has been examined. The allylsilanes were shown to provide an effective means for controlling product selectivity, and led to the formation of five- and six-membered ring products in 59–84% isolated yields.